WO2003002535A1

WO2003002535A1 - Cyclic diamine compounds bearing six-membered cyclic groups

Info

Publication number: WO2003002535A1
Application number: PCT/JP2002/006489
Authority: WO
Inventors: Tatsuhiko Kodama; Masahiro Tamura; Toshiaki Oda; Yukiyoshi Yamazaki; Masahiro Nishikawa; Takeshi Doi; Yoshinori Kyotani
Original assignee: Kowa Co., Ltd.
Priority date: 2001-06-29
Filing date: 2002-06-27
Publication date: 2003-01-09
Also published as: KR100842708B1; CA2451240A1; DE60209904D1; HK1065031A1; DE60209904T2; TWI236470B; CN1242992C; KR20040015738A; EP1403249B1; CN1520400A; JP4235103B2; EP1403249A4; ATE320416T1; JPWO2003002535A1; EP1403249A1; CA2451240C; ES2260438T3; US6509329B1

Abstract

Cyclic diamine compounds represented by the general formula (1), acid addition salts thereof, or hydrates of both: (1) [wherein A is a single bond or C≡C; X and Y are each CH or nitrogen; m is a number of 1 or 2; and n is a number of 1 to 5]. The compounds (1) have excellent inhibitory activities against cell adhesion and cell infiltration and are useful as preventive or therapeutic drugs for allergy, asthma, rheumatism, arteriosclerosis, and so on.

Description

Cyclic diamine compounds having a hame cyclic group

The present invention provides a cyclic diamine compound which has a cell adhesion inhibitory action and a cell infiltration inhibitory action and is useful as an anti-asthmatic agent, an anti-allergy agent, an anti-rheumatic agent, an anti-arteriosclerosis agent, an anti-inflammatory agent The present invention relates to a salt thereof and a pharmaceutical field containing the salt. Background art

In various inflammatory diseases, infiltration of leukocytes into inflammatory sites is observed. For example, infiltration of eosinophils into the bronchi of asthmatics (Ohkawa ra Y. et al., Am. J. Respir. Cell Mo 1. Biol. 12, 4-12 (1995)), blood vessels in atherosclerosis T. Infiltration of macrophages into T cells (Sakai A. et al., Arterioscler Thromb. Vas.e. Biol. 17, 310-316 (1997)), patients with atopic dermatitis (Wak ita H. et al., J. Cutan. Pat. 21, 33-39 (1994)) and infiltration of T cells and eosinophils into the skin of patients with contact dermatitis (S at oh T. et al. Eur. J. Immunol. 27, 85-91 (1997)), and various leukocyte infiltration into the synovium of patients with rheumatoid arthritis (Tak PP. Et al., Clin. Immu no 1 I mmu nopatho 1.77, 236-242 (1995)).

The infiltration of these leukocytes is triggered by cytokins, chemokines, lipids, complements, etc., which are produced locally in the inflammation (Albelda SM. Et al., FASE B J. 8, 504-512 (1994)). . Leukocytes in the activated bloodstream adhere to vascular endothelial cells via an interaction called a roll ring or tethering with the activated vascular endothelial cells as well. adhe si on) Thereafter, it infiltrates the vascular endothelium (tran smi gration) and infiltrates the site of inflammation (Springer TA. Et al., Annu. Rev. Phy sio 1.57, 827-872 (1995)). In this process, the adhesion between leukocytes and vascular endothelial cells is achieved by the immunoglobulin superfamily (ICAM-1, VCAM-1, etc.) and the selectin family (E-selectin, etc.) which are expressed on the cell surface by stimulation with cytokines. Integrin family (LFA-1, VLA-4, etc.) and various cell adhesion molecules such as CD44 play important roles (Clinical Immunity, 30, Supp 1.18 (1998)). It has been pointed out that this is related to enhanced expression of the molecule.

Therefore, drugs that can inhibit adhesion via cell adhesion molecules include allergic diseases such as bronchial asthma, dermatitis, rhinitis and conjunctivitis, rheumatoid arthritis, nephritis, inflammatory bowel disease, diabetes, and atherosclerosis. It is considered to be effective as a prophylactic and therapeutic agent for autoimmune diseases such as those and chronic inflammatory diseases. In fact, antibodies against leukocyte-side cell adhesion molecules such as LFA-1, Mac-1 and VLA-4 or their ligands such as ICAM-1, VCAM-1, P-selectin, and E-selectin on vascular endothelial cells. It has been reported that an antibody against cutin or the like suppresses infiltration of leukocytes into local inflammation in various animal disease models. For example, neutralizing antibodies against VCAM-1 and its counterpart receptor VLA-4 can delay the onset of diabetes in a NOD mouse model that spontaneously develops diabetes (Michie S A. et al., Curr Top. Micr ob iol. Immu no 1. 231, 65-83 (1998)). In addition, antibodies against VLA-4 or ICAM-1 and its counterpart LFA-1 inhibit eosinophil infiltration in guinea pig or mouse allergic conjunctivitis models (Ebihara et al., Currrent Eye Reagent). s. 19,20-25 (1999), Whitcup SM. et al., Clin. Immuno 1.93, 107-113 (1999)), a monoclonal antibody against VCAM-1 was used in mouse DSS-induced colitis. Suppresses leukocyte infiltration and delays the onset of colitis in a model (Sori an o A. et al., Lab. Invest. 80, 1541-1551 (2000)). Furthermore, anti-VLA-4 antibody and anti-CD44 antibody suppress its onset in a mouse collagen-induced arthritis model (Zeicl 1er A. et al., Autoimmunity 21, 245-252 (1995)). In addition, in mice deficient in these cell adhesion molecules, suppression of infiltration of leukocytes into inflamed tissues is observed as in the test of the inflammation model (Bend jell ouhl F. et al., Clin. E p.Immu no 1.119, 57-63 (2000), Wo 1 yniec WW. Et al., Am. J. Respir. Cell Mo 1. Biol. 18, 777-785 (1998), Bu ilard DC. et al., J. Immuno 1.157, 3153-3158 (1996)).

However, in the development using antibodies, not only is it difficult to administer orally because the antibodies are peptide polymers, but also the possibility of side effects such as allergic reactions based on antigenicity is considered as a problem.

On the other hand, various low-molecular-weight cell-adhesion-inhibiting compounds aimed at oral administration have been reported. Benzothiophene derivatives (Bosch 11 I DH. Et al., J. Med. Chem. 38, 4597-4614 (1995)), naphthylene derivatives (JP-A-10-147568), hydroxybenzoic acid derivatives (JP-A-10-182550), redanane (JP-A-10-67656), 2-substituted benzothiazole derivative (JP-A-2000-086641), condensed pyrazine compound (JP-A-2000-319277) ), 2,6-dialkyl-4-silyl-phenol (JP-T-2000-509070), etc., but the situation has not always been sufficiently achieved. The cyclic diamine compounds described in Japanese Patent Application Laid-Open Nos. 9-143075 and 92282/1992 do not exhibit a sufficient cell adhesion inhibitory effect, and further improvement in activity is desired.

Accordingly, an object of the present invention is to provide a substance which has cell adhesion and cell invasion inhibitory actions, and further has excellent anti-asthmatic action, anti-allergic action, anti-rheumatic action, anti-atherosclerotic action and anti-inflammatory action. And Disclosure of the invention

In view of such circumstances, the present inventors have conducted intensive studies to obtain a substance that inhibits cell adhesion and cell invasion. As a result, the compound represented by the following general formula (1) has an excellent cell adhesion inhibiting action. It has a cell invasion inhibitory effect and is useful as an anti-allergic agent, an anti-asthmatic agent, an anti-rheumatic agent, an anti-atherosclerotic agent, and an anti-inflammatory agent, and completed the present invention.

That is, the present invention provides the following general formula (1)

(1)

Wherein A represents a single bond or C 結合 C; X and Y each independently represent CH or a nitrogen atom; m represents a number of 1 or 2; n represents a number of 1 to 5 ]

A cyclic diamine compound represented by the formula: or an acid addition salt thereof or a hydrate thereof.

The present invention also provides a medicine containing the above cyclic diamine compound, an acid addition salt thereof or a hydrate thereof as an active ingredient.

The present invention further provides a pharmaceutical composition comprising the above-mentioned cyclic diamine compound, an acid addition salt thereof or a hydrate thereof, and a pharmaceutically acceptable carrier. Further, the present invention provides the use of the above-mentioned cyclic diamine compound, an acid addition salt thereof or a hydrate thereof for the production of a medicament.

Furthermore, the present invention is characterized in that an effective amount of the above-mentioned cyclic diamine compound, an acid addition salt thereof or a hydrate thereof is administered to a patient in need of treatment, and is characterized by cell adhesion and Z or cell infiltration. The present invention provides a method for treating a disease. BEST MODE FOR CARRYING OUT THE INVENTION

In the general formula (1), A represents a single bond or C≡C. X and Y each represent a CH or a nitrogen atom. Thus, the ring containing X and Y is a benzene, pyridine or pyrimidine ring. m represents 1 or 2, n represents a number of 1 to 5, and n is preferably a number of 1 to 3.

The acid addition salt of the compound (1) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples thereof include hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate. Acid addition salts of mineral acids such as benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, Acid addition salts of organic acids such as tartrate, citrate and acetate can be mentioned.

The compound (1) of the present invention may exist in the form of a solvate represented by a hydrate, and the solvate is also included in the present invention.

The compound (1) of the present invention can be produced, for example, according to the following reaction formula.

(1)

Wherein R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group, and A, X, Y, m and n are as defined above. the same]

That is, the carboxylic acid (2) or the aldehyde (3) is reduced to obtain an alcohol (4), which is reacted with a halogenating agent or a sulfonylating agent to give a compound (5), and the compound (5) is reacted with the compound (5). The compound (1) of the present invention can be obtained by condensing a cyclic diamine.

Examples of the halogen atom represented by R ² include a chlorine atom and a bromine atom. Examples of the alkylsulfonyloxy group include a methanesulfonyloxy group, and examples of the arylsulfonyloxy group include a p-toluenesulfonyloxy group. The reduction reaction of the carboxylic acid (2) or the aldehyde compound (3) is carried out, for example, in a tetrahydrofuran (THF) at room temperature, preferably at 0 ° C. to room temperature, at a reducing agent such as lithium aluminum hydride. The reaction is carried out for several seconds to several hours, preferably for 30 minutes, in the presence of.

Examples of the halogenating agent used for halogenating the alcohol (4) include thionyl chloride. On the other hand, methanesulfonyl chloride and the like are used as alkylsulfonylating agents, and p-toluenesulfonyl chloride and the like are used as arylsulfonylating agents. For the halogenation or sulfonylation of the alcohol (4), for example, in the case of thionyl chloride, the alcohol (4) is converted to a solvent such as chloroform, dichloromethane, ethyl acetate, ether, THF, dioxane, etc. On the other hand, in the case of methyl sulfonyl chloride or the like, the alcohol compound (4) can be prepared by converting the alcohol (4) in the presence of a base such as triethylamine or pyridin in the form of chloroform, dichloromethane, ethyl acetate, ether, HF, dioxane, pyridine or the like. The reaction is carried out by stirring in a solvent at a temperature of more than 120 to room temperature, preferably 0 to room temperature, for 1 hour to several days, preferably for 5 hours. The condensation reaction of compound (5) with cyclic diamine is carried out in a solvent such as N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), and acetonitrile in the presence of a base such as potassium carbonate at room temperature. The stirring is carried out at 0, preferably 50, for 1 hour to several days, preferably 5 hours.

The compound (1) of the present invention can be obtained by the above-mentioned method, and can be further purified, if necessary, by a conventional purification means such as a recrystallization method and column chromatography. If necessary, the desired salt or solvate can be prepared by a conventional method.

The thus-obtained compound (1) of the present invention, or an acid addition salt or solvate thereof, exhibits an excellent cell adhesion inhibitory action as shown in Examples described later, and exhibits asthma, arregii, rheumatism in animals including humans. It is useful as a medicament for treating or preventing arteriosclerosis, inflammation and the like. The medicament of the present invention comprises the compound (1), a salt thereof or a solvate thereof as an active ingredient. The dosage form is not particularly limited and can be appropriately selected depending on the purpose of treatment. Examples of the dosage form include oral preparations, injections, suppositories, ointments, inhalants, eye drops, nasal drops, and patches. These dosage forms can be produced by mixing a pharmaceutically acceptable carrier and using a conventional formulation method known to those skilled in the art.

When an oral solid preparation is prepared, the compound (1) of the present invention is usually treated with excipients and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, and the like. Tablets, coated tablets, granules, powders, capsules, etc. can be produced by the method. Such additives may be those commonly used in the art, such as lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose. Water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, cellulose propyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, Calcium phosphate, polyvinylpyrrolidone, etc .; disintegrants: dry starch, sodium alginate, agar powder, sodium hydrogencarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, lactose, etc. Can be exemplified by purified talc, stearate, borax, polyethylene glycol, etc. Examples of the flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.

When preparing a liquid preparation for oral use, a flavoring agent, a buffer, a stabilizing agent, a flavoring agent, etc. are added to the compound (1) of the present invention to produce an oral solution, a syrup, an elixir, etc. in a conventional manner. Can be. In this case, vanillin or the like can be used as a flavoring agent, sodium citrate or the like can be used as a buffer, and tragacanth, gum arabic, or gelatin can be used as a stabilizer.

When preparing an injection, a PH regulator, a buffer, a stabilizing agent, an isotonic agent, a local anesthetic, etc. are added to the compound of the present invention (1), and a subcutaneous, intramuscular or intravenous injection is prepared by a conventional method. Can be manufactured. In this case, pH adjuster and buffer were sodium citrate. Thorium, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Local anesthetics include proforce hydrochloride, lidocaine hydrochloride and the like. Examples of the isotonic agent include sodium chloride, glucose and the like.

When preparing suppositories, the compound (1) of the present invention may be formulated with a pharmaceutical carrier known in the art, for example, polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, and, if necessary, Tween (registered trademark). After adding a surfactant such as described above, it can be produced by a conventional method.

When preparing an ointment, a base, a stabilizer, a wetting agent, a preservative and the like usually used for the compound (1) of the present invention are blended as required, and mixed and formulated by a conventional method. Examples of the base include liquid paraffin, white petrolatum, beeswax, octyldodecyl alcohol, paraffin and the like. Examples of the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate and the like.

In addition to the above, inhalants, eye drops, and nasal drops can be prepared by conventional methods.

The dosage of the medicament of the present invention varies depending on age, body weight, symptoms, administration form, number of administrations, and the like. Usually, the amount of the compound of the present invention (1) is 1 to 100 mg / day for an adult. Is preferably orally or parenterally administered once or divided into several times. Example

Next, the present invention will be further described with reference to examples, but the present invention is not limited thereto.

Production Example 1

Synthesis of 2- (3,4,5-trimethoxyphenyl) ethyl benzoate:

Suspension of 3,4,5-trimethoxyphenylboronic acid (639mg) and ethyl 2-bromobenzoate (479mg) are suspended in a mixed solvent of toluene (20mL) and THF (15mL), and 2M sodium carbonate (6mL) And tetrakis (triphenylphosphine) palladium (0) (175 mg) were added. The mixture was stirred overnight at 9 Ot: under an argon atmosphere, and ethyl acetate was added to separate the organic layer. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound.

Yield: 655mg (69%)

Ή-NMR (400MHz, CDC 1 3) δ: 1. 04 (t, 3H, 1 = 7. 2 Hz), 3. 86 (s, 6H), 3. 89 (s, 3 H), 4. 12 (q, 2H, J = 7.2Hz), 6.54 (s, 2H), 7.40-7.42 (m, 2H), 7.51 (t, 1H, J = 7.8Hz) , 7.77 (d, 1 H, J = 6.8 Hz

)

Production Example 2

Synthesis of 2- (3,4,5-trimethoxyphenyl) benzyl alcohol:

Dissolve 2- (3,4,5-trimethoxyphenyl) ethyl benzoate (655 mg) in THF (20 mL) 'and add lithium aluminum hydride (80 mg) at 0 under argon atmosphere. The mixture was stirred at 0 as it was for 1 hour. A small amount of water and then sodium sulfate are added to the reaction solution, the mixture is filtered through celite, and the filtrate is concentrated under reduced pressure. The crystals were recrystallized from ethyl acetate-hexane to give the title compound.

Yield: 63 Omg (theoretical)

Ή-NMR (400MHz, CDC 1 3) δ: 3. 85 (s, 6 H), 3. 90 (s, 3Η), 4. 61 (s, 2H), 6. 61 (s, 2 H), 7.26-7.39 (m, 3H), 7.53 (d, 1H, J = 6.8Hz)

Production Example 3

Synthesis of 2- (3,4,5-trimethoxyphenyl) benzyl chloride:

Dissolve 2- (3,4,5-trimethoxyphenyl) benzyl alcohol (63 Omg) in chloroform (10 mL), add thionyl chloride (0.153 mL) at 0 ° C, and after 30 minutes It returned to room temperature and stirred for 4 hours. After the completion of the reaction, the reaction solution was washed with water and saturated saline, and dried over sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from chloroform-hexane to give the title compound.

Yield: 615mg (theoretical)

Ή-NMR (40 OMH z, CDC 1 3) δ 3. 87 (s, 6H), 3. 90 (s, 3H), 4. 53 (s, 2H), 6. 66 (s, 2 H), 7.29—7.32 (m, 1Η), 7.34-7.39 (m, 2H), 7.50—7.52 (m, 1H)

Example 1

Synthesis of N, N'-bis [2- (3,4,5-trimethoxyphenyl) benzyl] piperazine dihydrochloride: eO 丫, OMe

OMe

2- (3,4,5-Trimethoxyphenyl) benzyl chloride (298 mg) and piperazine (43 mg) were dissolved in DMF (5 mL), and potassium carbonate (138 mg) was added. The mixture was stirred at 80 for 4 hours and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to give the free base of the title compound. This was dissolved in ethyl acetate, and a 4 M solution of hydrogen chloride in ethyl acetate was added to obtain a dihydrochloride.

Yield: 238mg (74%)

Ή-NMR (400MHz, DMSO - d 6, 120) 6: 2. 95 (br, 8H), 3. 77 (s, 6H), 3. 80 (s, 12 H), 3. 99 (s, 4H ), 6.59 (s, 4H), 7.28-7.30 (m, 2H), 7.37-7.42 (m, 4H), 7.80 (d, 2H, J = 6.3Hz) )

m / z (EI): 598 [M ⁺ ]

Example 2

N, '-bis [2- (3,4,5-trimethoxyphenyl) benzyl] homopi

Synthesis of dihydrochloride:

2- (3,4,5-trimethoxyphenyl) benzyl chloride (307mg) And homopirazine (53 mg) were reacted in the same manner as in Example 1 to obtain a free base of the title compound. This was converted to the dihydrochloride as in Example 1.

Yield: 18 lmg (51%)

Ή-NMR (400MHz, DMSO- d 6, 120 in) δ: 2. 20 (br, 2H), 3. 1 1 (br, 4H), 3. 39 (br, 4H), 3. 77 (s, 6 H), 3.81 (s, 12H), 4.20 (s, 4H), 6.58 (s, 4H), 7.29-7.31 (m, 2H), 7.39—7 .44 (m, 4H), 7.99 (d, 2H, J = 7.8Hz)

mZz (E I): 6 12 [M +]

Production Example 4

Synthesis of 3- (3,4,5-trimethoxyphenyl) ethyl benzoate:

3,4,5-Trimethoxyphenylporonic acid (3.7 g) and ethyl 3-bromobenzoate (4.02 g) were reacted in the same manner as in Production Example 1 to obtain the title compound.

Yield: 5.09 g (92%)

Ή-NMR (400 MHz, CDC δ: 1.42 (t, 3H, 7

Hz), 3.90 (s 3H), 3.94 (s, 6H), 4.41 (q, 2H, 1 = 7.1 Hz), 679 (s, 2H), 7.50 (t, 1H, J = 7.8Hz, 7.73 (dt 1H, J = 7.1Hz, 1.5Hz), 8.01 (dt, 1H, J = 7.8Hz 1.4Hz), 8. 23 (t, 1H, J = 1.8 Hz) Production Example 5

Synthesis of 3- (3,4,5-trimethoxyphenyl) benzyl alcohol:

3- (3,4,5-Trimethoxyphenyl) ethyl benzoate (5.09 g) was treated in the same manner as in Production Example 2 to obtain the title compound.

Yield: 4.25 g (97%)

Ή-NMR (400MHz, CDC 1 3) (5: 1. 87 (t, 1 H, J = 6. 0 Hz), 3. 89 (s, 3H), 3. 92 (s, 6 H), 4 .76 (d, 1H, J = 5.6Hz), 6.77 (s, 2H), 7.34 (d, 1H, J = 7.4Hz), 7.42 (t, 1H, J = 7.5Hz), 7.48 (d, 1H, J = 7.6Hz), 7.55 (s, 1H)

Production Example 6

Synthesis of 3- (3,4,5-trimethoxyphenyl) benzyl chloride:

3- (3,4,5-Trimethoxyphenyl) benzyl alcohol (1.21 g) was treated in the same manner as in Preparation Example 3 to obtain the title compound.

Yield: 893mg (69.2%)

Ή-NMR (400MHz, CDC 1 3) δ: 3. 87 (s, 3 H), 3. 90 (s, 6H), 4. 62 (s, 2H), 6. 75 (s, 2H), 7 .33 (d, 1H, J = 7.6Hz), 7.39 (t, 1H, J = 7.7Hz), 7.48 (d, 1H, J = 7.6Hz), 7.54 ( s, 1 H)

Example 3

Synthesis of N, N'-bis [3- (3,4,5-trimethoxyphenyl) benzyl] piperazine:

3- (3,4,5-Trimethoxyphenyl) benzyl chloride (120 mg) was reacted with piperazine (17 mg) in the same manner as in Example 1 to obtain the title compound as a free base.

Yield: 78mg (65%)

Ή-NMR (400MHz, CDC 1 3) 6: 2. 55 (br, 8 H), 3. 5 8 (s, 4H), 3. 88 (s, 6H), 3. 92 (s, 12 H) , 6.77 (s, 4H), 7.30 (d, 2H, J = 7.6Hz), 7.36 (t, 2H, J = 7.5Hz), 7.43 (d, 2H, J = 7.6Hz), 7.48 (br, 2H)

m / z (EI): 671 [M ⁺ ]

Example 4

Synthesis of N, N'-bis [3- (3,4,5-trimethoxyphenyl) benzyl] homopiperazine:

3- (3,4,5-Trimethoxyphenyl) benzyl chloride (184 mg) was reacted with homopidazine (52 mg) in the same manner as in Example 1 to obtain the title compound as a free base.

Yield: 1 59mg (87%)

Ή-NMR (400MHz, CDC 1 3) δ 1. 89 - 1. 92 (m, 2 H), 2. 80 - 2. 86 (m, 8 H), 3. 76 (s, 4H), 3. 89 (s, 6H), 3.92 (s, 12H), 6.79 (s, 4H), 7.31—7.45 (m, 6H), 7.57 (s, 2H)

m / z (EI): 685 [M ⁺ ]

Production Example 7

Synthesis of 4- (3,4,5-trimethoxyphenyl) ethyl benzoate:

3,4,5-Trimethoxyphenylporonic acid (2.01 g) and 4-ethyl bromobenzoate (2.29 g) were reacted in the same manner as in Production Example 1 to obtain the title compound. Yield: 2.99 g (95%)

Ή-NMR (400MHz, CDC 1 3) 5: 1. 42 (t, 3H, J = 7. 2 Hz), 3. 90 (s, 3H), 3. 94 (s, 6 H), 4. 38 (q, 2H, J = 7.2Hz), 6.81 (s, 2H), 7.62 (d, 2H, J = 8.2Hz), 8.10 (d, 2H, J = 8 .2Hz)

Production Example 8

Synthesis of 4- (3,4,5-trimethoxyphenyl) benzyl alcohol:

41 One (3,4,5-trimethoxyphenyl) ethyl benzoate (2.99 g) was treated in the same manner as in Production Example 2 to obtain the title compound.

Yield: 1.83 g (71%)

Production Example 9

Synthesis of 4- (3,4,5-trimethoxyphenyl) benzyl chloride:

4- (3,4,5-Trimethoxyphenyl) benzyl alcohol (1.83 g) was treated in the same manner as in Preparation Example 3 to obtain the title compound.

Yield: 1.65 g (84%)

Ή-NMR (40 OMH z, CDC 1 3) (5: 3. 90 (s, 3 H), 3. 93 (s, 6Η), 4. 65 (s, 2Η), 6. 77 (s, 2 Η), 7.46 (d, 2H, J = 8.0Hz), 7.55 (d, 2H, J = 8.0Hz)

Example 5

Synthesis of N, N'-bis [4_ (3,4,5-trimethoxyphenyl) benzyl] piperazine'2 methanesulfonate:

4- (3,4,5-Trimethoxyphenyl) benzyl chloride (442 mg) and piperazine (65 mg) were reacted in the same manner as in Example 1 to obtain the free base of the title compound. This was dissolved in methanol and methanesulfonic acid was added to obtain the title compound.

Yield: 36 Omg (61%)

Ή-NMR (400 MHz, DMSO—, 120 ° C) δ: 2.49 (s, 6H), 3.21 (s, 8H), 3.75 (s, 6H), 3.87 (s , 12H), 4.17 (s, 4H), 6.91 (s, 4H), 7.53 (d, 4H, J = 8.2 Hz), 7.68 (d, 4H, J = 8.2 Hz) )

m / z (EI): 598 [M +] Example 6

N, N'-bis [4- (3,4,5-trimethoxyphenyl) benzyl] homopi

2 Synthesis of maleate:

41 One (3,4,5-trimethoxyphenyl) benzyl chloride (85 mg) was reacted with homopidazine (83 mg) in the same manner as in Example 1 to obtain a free base of the title compound. This was dissolved in methanol and maleic acid was added to obtain the title compound. Yield: 224mg (32%)

Ή-NMR (400 MHz, DMS〇—d ₆ , 120) δ: 2.00—2.0 6 (m, 2H), 3.10 (t, 4Η, J = 5.7 Hz), 3.14 ( s, 4H), 3.76 (s, 6H), 3.88 (s, 12H), 4.08 (s, 4H), 6.13 (s, 4H), 6.91 (s, 4H), 7.49 (d, 4H, J = 8.2Hz), 7.67 (d, 4H, J = 8.2Hz)

m / z (EI): 612 [M ⁺ ]

Production Example 10

Synthesis of 2- (3,4,5-trimethoxyphenyl) ethynyl nicotinate:

3,4,5-Trimethoxyphenylporonic acid (694 mg) was reacted with 2-ethyl ethyl nicotinate (608 mg) in the same manner as in Production Example 1 to obtain the title compound. Yield: 799mg (77%)

Ή-NMR (400MHz, CDC 1 3) δ 1. 10 (t, 3H, J = 7. 2 Hz), 3.89 (s 9H), 4.19 (q, 2 H, J = 7.2 Hz) 6.79 (s 2H) 7.34 (dd, 1 H, J = 7.8 Hz, 4. 8Hz) 8.06 (cld, 1H, J = 7.8Hz 1.7Hz), 8.75 (dd, 1 HJ = 4.8Hz, 1.7Hz)

Production Example 11

Synthesis of 3-hydroxymethyl_2- (345-trimethoxyphenyl) pyridine:

2- (3,45-Trimethoxyphenyl) ethyl nicotinate (468 mg) was treated in the same manner as in Production Example 2 to obtain the title compound.

Yield: 293mg (72%)

Ή-NMR (400MHz, CDC 1 3) δ 3. 90 (s, 9H), 4. 72 (s, 2H), 6. 83 (s 2H) 7. 32 (dd 1H J = 7. 9Hz, 4. 8Hz) 7.92 (dd, 1 H 1 = 7.9Hz, 1.7Hz), 8.62 (dd 1H, J = 4.8Hz 1.7Hz)

Production Example 12

Synthesis of 3-chloromethyl-2- (3,45-trimethoxyphenyl) pyridine

3-Hydroxymethyl-2- (3,45-trimethoxyphenyl) pyri (293 mg) was treated in the same manner as in Production Example 3 to obtain the title compound.

Yield: 31 lmg (theoretical) Example 7

Synthesis of N, N'-bis [[2- (3,4,5 trimethoxyphenyl) pyridine-13-yl] methyl] pidazine:

3-Chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (24 lmg) and piperazine (35 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.

Yield: 96mg (40%)

Ή-NMR (400MHz, CDC 1 3) δ 2. 4 5 (br, 8 H), 3. 8 9 (s, 12 H), 3. 90 (s, 6H), 6. 92 (s, 4H) , 7.25 (dd, 2H, J = 7.8Hz, 4.9Hz), 7.27 (s, 4H), 7.79 (dd, 2H, J = 7.8Hz, 1.7Hz), 8. 58 (dd, 2H, J = 4.9Hz, 1.7Hz)

m / z (EI): 600 [M ⁺ ]

Example 8

Synthesis of N, N'-bis [[2- (3,4,5-trimethoxyphenyl) pyridin-3-yl] methyl] homopyrazine:

3-chloromethyl-2_ (3,4,5-trimethoxyphenyl) pyridine (3 lmg) was reacted with homopyrazine (53 mg) in the same manner as in Example 1, and The compound was obtained as a free base.

Yield: 1 59mg (52%)

Ή-NMR (400MHz, CDC 1 3) δ: 1. 68- 1. 73 (m, 2 H), 2. 57 (s, 4H), 2. 63 (t, 4H, J = 6. 0Hz), 3.89 (s, 12H), 3.90 (s, 6H), 6.77 (s, 4H), 7.26 (dd, 2

H, J = 7.7 Hz, 4.6 Hz), 7.27 (s, 4H), 7.90 (dd, 2H, J = 7.7 Hz, 1.7 Hz), 8.55 (dd, 2H, J = 4.6 hz,

(I. 7Hz)

m / z (E I): 6 14 [M +]

Production Example 13

Synthesis of 2- (3,4,5-trimethoxyphenyl) ethyl isonicotinate:

3,4,5-Trimethoxyphenylboronic acid (15.29 g) and ethyl 2-chloroisonicotinate (13.39 g) were reacted in the same manner as in Production Example 1 to obtain the title compound.

Yield: 19.36 g (85%)

Ή-NMR (400 MHz, CDC 1 3) <5: 1. 45 (t, 3H, J = 7. 0 Hz), 3. 92 (s, 3H), 3. 99 (s, 6 H), 4 46 (q, 2H, J = 7.0 Hz), 7.30 (s, 2H), 7.76 (dd, 1 H, J = 5.1 Hz, 1.6 Hz), 8.24 (dd, 1 H, J = 1.6 Hz, 0.8 Hz), 8.81 (dd, 1H, J = 5.1 Hz, 0.8 Hz)

Production Example 14

Synthesis of 4-hydroxymethyl-2- (3,4,5-trimethoxyphenyl) pyridine:

2- (3,4,5-Trimethoxyphenyl) ethyl isonicotinate (17.21 g) was treated in the same manner as in Preparation Example 2 to obtain the title compound.

Yield: 1.78 g (79%)

Ή-NMR (400MHz, CDC 1 3) δ 3. 90 (s, 3 H), 3. 95 (s, 6H) '4. 79 (s, 2H), 7. 19 (d, 1 H, J = 5.1 Hz), 7.21 (s, 2H), 7.66 (s, 1H), 8.60 (d, 1H, J = 5.1 Hz)

Production Example 15

Synthesis of 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine

4-Hydroxymethyl-1- (3,4,5-trimethoxyphenyl) pyridine (8.26 g) was treated in the same manner as in Production Example 3 to obtain the title compound.

Yield: 7.78 g (88%)

Ή-NMR (400 MHz, CDC 1 3) 6 3. 91 (s, 3H), 3. 97 (s, 6H), 4. 61 (s, 2H), 7. 24 (s, 2 H), 7 26 (d, 1H, J = 5.1 Hz), 7.68 (s, 1H), 8.67 (d, 1H, J = 5.1 Hz)

Example 9

Synthesis of N, N'-bis [[2- (3,4,5-trimethoxyphenyl) pyridine-14-yl] methyl] pidazine:

4-Chloromethyl-1- (3,4,5-trimethoxyphenyl) pyridine (10 Omg) and piperazine (15 mg) were reacted in the same manner as in Example 1 to give the title compound as a free base. Obtained.

Yield: 93mg (91%)

Ή-NMR (400MHz, CDC 1 3) <5 2. 55 (br, 8H), 3. 5 9 (s, 4H), 3. 90 (s, 6H), 3 97 (s, 12H), 7. 22 (d, 2H, J = 5.1 Hz), 7.24 (s 4H), 7.64 (s, 2H), 8.59 (d, 2H, J = 5.1 Hz)

m / z (EI): 600 [M ⁺ ]

Example 10

Synthesis of N, N'-bis [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] homopirazine:

4-Chloromethyl-1- (3,4,5-trimethoxyphenyl) pyridine (10 Omg) and homopyrazine (17 mg) were reacted in the same manner as in Example 1 to give the title compound as a free base. Obtained.

Yield: 10 lmg (97%)

Ή-NMR (400 MHz, CDC 1 3) δ 1. 85- 1. 88 (m, 2 H), 2. 73 -2. 90 (m, 8 H), 3. 72 (s, 4H), 3 89 (s, 6H), 3.96 (s, 12H) '7.24 (br, 6H), 7.66 (s, 2H), 8.58 (d, 2H, J = 4.9Hz ) m / z (EI): 614 [M ⁺ ]

Production Example 16

Synthesis of 5-(3, 4, 5-trimethoxyphenyl) ethynyl nicotinate:

3,4,5-Trimethoxyphenylporonic acid (6.36 g) and ethyl 5-bromonicotinate (6.90 g) were reacted in the same manner as in Production Example 1 to obtain the title compound. Yield: 7.19 g (76%)

Ή-NMR (400MHz, CDC 1 3) δ 1. 44 (t, 3 Η, J = 7. 1 Hz), 3. 91 (s, 3H), 3. 95 (s, 6 H), 4. 46 (q, 2H, 3 = 7.1 Hz), 6.79 (s, 2H), 8.44 (t, 1H, J = 2.1 Hz), 8.96 (d, 1H, J = 2. 1 Hz), 9.18 (d, 1 H, J = 1.8 Hz)

Production Example 17

Synthesis of 3-hydroxymethyl-5_ (3,4,5-trimethoxyphenyl) pyridine:

Ethyl 5- (3,4,5-trimethoxyphenyl) nicotinate (79 g) was treated in the same manner as in Production Example 2 to obtain the title compound.

Yield: 3.83 g (61.3%)

Ή-NMR (400MHz, CDC 1 3) δ: 3. 88 (s, 3H): 3. 89 (s, 6H), 4. 39 (br, 1 H), 4. 80 (s, 2 H), 6 72 (s

2H), 7.89 (t, 1H, 1.2Hz), 8.47 (d, 1H, = 2 1 Hz), 8.63 (d, 1H, J = 2.2 Hz)

Production Example 18

Synthesis of 3-chloromethyl-5- (3,4,5-trimethoxyphenyl) pyridine

3-Hydroxymethyl-5- (3,4,5-trimethoxyphenyl) pyridine (2.85 g) was treated in the same manner as in Production Example 3 to obtain the title compound.

Yield: 1.97 g (65%)

Ή-NMR (400 MHz, CDC 1 3) δ: 3. 90 (s, 3 H), 3. 94 (s, 6H), 4. 67 (s, 2H), 6. 75 (s, 2 H) , 7.87 (t, 1 H, J = 2.1 Hz), 8.59 (d, 1 H, J = 2.0 Hz), 8.76 (d, 1H, J = 2.1 Hz)

Example 1 1

Synthesis of N, N'-bis [[5- (3,4,5-trimethoxyphenyl) pyridin-3-yl] methyl] pidazine:

3-Chloromethyl-5- (3,4,5-trimethoxyphenyl) pyridine (7 Omg) and piperazine (lOmg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.

Yield: 47mg (65%)

Ή-NMR (400MHz, CDC 1 3) δ: 2. 53 (br, 8H), 3. 5 9 (s, 4H), 3.90 (s, 6H), 3.94 (s, 12H), 6.76 (s, 4H), 7.79 (s, 2H), 8.51 (s, 2H) H), 8.70 (s, 2 H)

mZz (E I): 600 [M +]

Example 12

Synthesis of N, N'-bis [[5_ (3,4,5-trimethoxyphenyl) pyridin-3-yl] methyl] homopyrazine:

3_Chloromethyl-1- (3,4,5-trimethoxyphenyl) pyridine (7 Omg) and homopidazine (12 mg) were reacted in the same manner as in Example 1, and the title compound was used as a free base. Obtained.

Yield: 56mg (76%)

Ή-NMR (400MHz, CDC ") δ 1.85 (br, 2H), 2.73 (br, 4H), 2.79 (t, 4H, J 5.9Hz), 3.73 (s, 4 H), 3.90 (s, 6H), 3.94 (s12Η), 6.76 (s, 4H) _: 7.82 (s, 2H), 8.53 (d, 2H, J = 2 .0Hz) 8.68 (d: 2H, J = 2.1Hz)

m / z (EI): 614 [M ⁺ ]

Production Example 19

Synthesis of 6- (3,4,5-trimethoxyphenyl) picolinate:

3,4,5-Trimethoxyphenylporonic acid (837 mg) was reacted with 6-chloroethyl picolinate (733 mg) in the same manner as in Production Example 1 to obtain the title compound. Yield: 929mg (74%)

Ή-NMR (400 MHz, CDC 1,) (5: 1.46 (t, 3H, 7.1

Hz), 3.90 (s, 3H), 3.98 (s, 6H), 4.49 (q, 2H, J = 7. lHz), 7.30 (s, 2H), 7.84— 7.94 (m, 2 H), 8.03 (dd, 1 H, J = 7.2 Hz, 1.5 Hz)

Production Example 20

Synthesis of 2-hydroxymethyl-6- (3,4,5-trimethoxyphenyl) pyridine:

6- (3,4,5-Trimethoxyphenyl) picolinic acid ethyl ester (929 mg) was treated in the same manner as in Preparation Example 2 to obtain the title compound.

Yield: 698mg (87%)

Ή-NMR (400MHz, CDC 1 3) (5: 3. 91 (s, 3H), 3. 97 (s, 6H), 4. 82 (s, 2H), 7. 17 (d, 1 H, J = 7.6Hz), 7.24 (s, 2H), 7.60 (d, 1H, J = 7.8Hz), 7.75 (t, 1H, J = 7.8Hz)

Production Example 21

Synthesis of 2-chloromethyl-6- (3,4,5-trimethoxyphenyl) pyridine

2-Hydroxymethyl-6_ (3,4,5-trimethoxyphenyl) pyridine (698 mg) was treated in the same manner as in Production Example 3 to obtain the title compound. Yield: 727mg (99%)

Example 13

Synthesis of N, N'-bis [[6- (3,4,5-trimethoxyphenyl) pyridine-1-yl] methyl] pidazine · 2 maleate:

2-Chloromethyl-1 6- (3,4,5-trimethoxyphenyl) pyridine (353 mg) and piperazine (52 mg) were reacted in the same manner as in Example 1 to obtain a free base. This was dissolved in methanol and converted to the title compound by adding maleic acid.

Yield: 403mg (81%)

Ή-NMR (400MHz, DMSO- d 6, 120 ° C) δ: 3. 14 (s, 8 H), 3. 79 (s, 6H), 3. 89 (s 12H), 4. 13 (s, 4Η) 6.11 (s, 4H), 7.36-7.38 (m, 2H), 7.37 (s, 4H), 7.80-7.86 (m, 4H)

m / z (E I): 600 [M +]

Example 14

Synthesis of N, N'-bis [[6- (3,4,5-trimethoxyphenyl) pyridine-1- [2-yl] methyl] homopirazine / 2 fumarate:

2_Chloromethyl_6- (3,4,5-trimethoxyphenyl) pyridine (374 mg) and homopidazine (64 mg) were reacted in the same manner as in Example 1 to give free The base was obtained. This was dissolved in methanol and converted to the title compound by adding fumaric acid.

Yield: 293mg (58%)

Ή-NMR (400 MHz, DMSO—d ₆ , 120) δ: 1.86 (qu int, 2H, J = 5.9 Hz), 2.94 (s, 4H), 2.94 (t, 4H, J = 5.9 Hz), 3.77 (s, 6 H), 3.87 (s, 12 H), 3.94

(s, 4H), 6.63 (s, 4H), 7.35 (s, 4H), 7.36 (d, 2H, J = 5.4 Hz), 7.71 (d, 2H, J = 6.8Hz), 7.76 (t, 2H, J = 7.6Hz)

m / z (E I): 614 [M +]

Production Example 22

Synthesis of 4-bromopyridine-N-oxide:

4-Bromopyridine hydrochloride (2.88 g) and potassium carbonate (2.46 g) were added to dichloromethane (50 mL), and the mixture was stirred for 30 minutes. Then, 3-chloroperbenzoic acid (5.11 g) was added. The mixture was stirred at room temperature for 2 hours. Furthermore, 3-chloroperbenzoic acid (3.0 g) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction solution, and the mixture was stirred and insoluble matter was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography- (ethyl acetate: hexane = 50: 1 → chloroform: methanol = 20: 1) to obtain the title compound.

Yield: 2.25 g (87%) Preparation 23

Synthesis of 4- (3,4,5-trimethoxyphenyl) pyridine-N-oxide:

3,4,5-Trimethoxyphenylboronic acid (2.49 g) was reacted with 4-bromopyridine-N-butoxide (2.25 g) in the same manner as in Preparation Example 1 to obtain the title compound. .

Yield: 2.69 g (88%)

Ή-NMR (400MHz, CDC 1 3) 6: 3. 90 (s, 3H), 3. 93 (s, 6H), 6. 76 (s, 2H), 7. 47 (d, 2H, J = 7 1 Hz), 8.25 (d, 2H, J = 7.1 Hz)

Production Example 24

Synthesis of 2- (4-, 3-, 5-trimethoxyphenyl) pyridine:

At 0 ° C., 4- (3,4,5-trimethoxyphenyl) pyridine-N-oxide (27 mg) was added with oxychloride phosphorus (2 mL), and the mixture was stirred at 100 for 5 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and neutralized at 0 ° C. with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound.

Yield: 22mg (77%)

Ή-NMR (40 OMH z, CDC 1 3) δ: 3. 9 1 (s, 3H), 3. 94 (s, 6H), 6. 79 (s, 2Η), 7. 39 (d, 1 Η , J = 4.9 Hz), 7.49 (s, 1 H), 8.41 (d, 1 H, J = 5.3 Hz)

Production Example 25 Synthesis of 2-Methyl-4-1 (3,4,5-trimethoxyphenyl) pyridine

Nickel chloride (3.0 mg) was added to THF (1 mL) under an argon atmosphere. A solution of 0.93M-bromomethylmagnesium in THF (0.38 mL) was slowly added dropwise, and then 2_chloro mouth_4- (3,4,5-trimethoxyphenyl) pyridine (5 Omg) in THF (5 mg) was added. 2 mL) solution was slowly added dropwise. After stirring for 10 minutes at 0, the mixture was stirred at 70 for 1.5 hours. At 0, a small amount of dilute hydrochloric acid was added, and the mixture was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 15: 1) to give a blue powder. The compound was obtained.

Yield: 35mg (75%)

Ή-NMR (40 OMHz, CDC 1 3) δ: 2. 62 (s, 3 H), 3. 90 (s, 3H), 3. 94 (s, 6H), 6. 81 (s, 2 H) , 7.27 (d, 1 H, J = 5.1 Hz), 7.32 (s, 1 H), 8.52 (d, 1 H, J = 5.3 Hz)

Production Example 26

Synthesis of 4- (3,4,5-trimethoxyphenyl) pyridine-2--2-carboxylic acid:

2-Methyl-1- (3,4,5-trimethoxyphenyl) pyridine (830 mg) was dissolved in pyridine (4 mL), selenium dioxide (852 mg) was added, and the mixture was stirred at 120 t for 3 days. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure. The residue was dissolved in chloroform and precipitated by adding hexane to obtain the title compound.

Yield: 587mg (64%)

Production Example 27

Synthesis of methyl 4- (3,4,5-trimethoxyphenyl) pyridine-2-carboxylate:

4- (3,4,5-Trimethoxyphenyl) pyridine-di-2-carboxylic acid (587 mg) is dissolved in methanol (2 mL) and dichloromethane (8 mL), and the resulting solution is dissolved in 1-ethyl-3- (3- (Dimethylaminopropyl) carposimide 'hydrochloride (583 mg) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and the organic layer was washed with water and saturated saline. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to obtain the title compound.

Yield: 543mg (88%)

Production Example 28

Synthesis of 2-hydroxymethyl-41- (3,4,5-trimethoxyphenyl) pyridine:

4-Methyl (3,4,5-trimethoxyphenyl) pyridine-12-potassium methyl ribonate (543 mg) was treated in the same manner as in Preparation Example 2 to obtain the title compound.

Yield: 429mg (87%)

Ή-NMR (400MHz, CDC 1 3) δ: 1. 32 (br, 1H), 3. 9 0 (s, 3H), 3.94 (s, 6H), 4.83 (s, 2H), 6.82 (s, 2H), 7.38 (d, 1H, J = 4.9Hz), 7.42 (s, 1 H), 8.58 (d, 1 H, J = 5.1 Hz)

Production Example 29

Synthesis of 2-chloromethyl-41- (3,4,5-trimethoxyphenyl) pyridine

2-Hydroxymethyl-1- (3,4,5-trimethoxyphenyl) pyridine (429 mg) was treated in the same manner as in Production Example 3 to obtain the title compound.

Yield: 374mg (82%)

Example 15

Synthesis of N, Ν'-bis [[4- (3,4,5-trimethoxyphenyl) pyridine-1-yl] methyl] pidazine:

2-Chloromethyl-1- (3,4,5-trimethoxyphenyl) pyridine (195 mg) and piperazine (28 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.

Yield: 15 Omg (79%)

Ή-NMR (400MHz, CDC 1 3) 5: 2. 63 (br, 8H), 3. 7 4 (s, 4H), 3. 90 (s, 6H), 3. 94 (s, 12 H), 6.82 (s, 4H), 7.34 (dd, 2H, J = 5. lHz, 1.7Hz), 7.56 (s, 2H), 8.58 (d, 2H, J = 5.4Hz)

m / z (E I): 600 [M +]

Example 16

Synthesis of N, N'-bis [[4- (3,4,5-trimethoxyphenyl) pyridine-1-yl] methyl] homopidazine:

2-chloromethyl-4_ (3,4,5-trimethoxyphenyl) pyridine (1

95 mg) and homopidazine (32 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.

Yield: 177mg (91%)

_{- NMR (400MHz, CDC 1 3} ) (5: 1. 88- 1. 91 (m, 2 H), 2. 84- 2. 89 (m, 8H), 3. 88 (s, 4H), 3. 90 (s, 6H

), 3.94 (s, 12H), 6.83 (s, 4H), 7.33 (dd, 2H, J = 5.1Hz, 1.7Hz), 7.66 (d, 2H, J = l. 2Hz), 8.

55 (d, 2 H, J = 4.6 Hz)

/ z (E I): 6 14 [M +]

Production example 30

6— (3,4,5-trimethoxyphenyl) Synthesis of ethyl nicotinate:

3,4,5-Trimethoxyphenylboronic acid (1.16 g) and 6-chloroethyl nicotinate (1.02 g) were reacted in the same manner as in Production Example 1 to obtain the title compound.

1.42 g (82%)

'Η- NMR (400 MHz, CDC 1 3) (5: 1. 43 (t, 3H, J = 7. 2 Hz), 3.92 (s, 3H), 3.98 (s, 6H), 4.44 (q, 2H, J = 7.2Hz), 7.32 (s, 2H), 7.76 (d, 1H, J = 8.3Hz), 8.33 (dd, 1H, J = 8.2Hz, 2.2Hz), 9.26 (d, 1H, J = 2.2Hz)

Production Example 31

Synthesis of 5-hydroxymethyl-2- (3,4,5-trimethoxyphenyl) pyridine:

Ethyl 6- (3,4,5-trimethoxyphenyl) nicotinate (658 mg) was treated in the same manner as in Production Example 2 to obtain the title compound.

Yield: 482mg (85%)

Ή-NMR (400MHz, CDC 1 3) δ: 3. 91 (s, 3H), 3. 97 (s, 6Η), 4. 76 (s, 2H), 7. 23 (s, 2 H), 7 68 (d, 1H, J = 7.4 Hz), 7.78 (dd, 1 H, J = 7.4 Hs, 2.3 Hz), 8.63 (d, 1 H, J = 2.3 Hz)

Production Example 32

Synthesis of 5-chloromethyl-1- (3-, 4,5-trimethoxyphenyl) pyridine

5-Hydroxymethyl-2- (3,4,5-trimethoxyphenyl) pyridine (685 mg) was treated in the same manner as in Preparation Example 3 to obtain the title compound.

Yield: 717mg (theoretical) Example 1

Synthesis of Ν, Ν'—bis [[2— (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] piperazine:

5-Chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (294 mg) and piperazine (43 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.

Yield: 1 98mg (66%)

Ή-NMR (400 MHz, CDC 1 3) <5: 2. 53 (br, 8H), 3. 5 7 (s, 4H), 3. 90 (s, 6H), 3. 96 (s, 12H) ,, 7.36 (s, 4H), 7.65 (d, 2H, J = 8.1 Hz), 7.72 (dd, 2H, J = 8.1 Hz, 2.1 Hz), 8.58 (d , 2H, J = 2.1 Hz) m / z (EI): 600 [M +]

Example 18

Synthesis of N, N'-bis [[2- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] homopiperazine:

5-Chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (294 mg) and homopidazine (50 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base. . Yield: 1 53mg (49%)

Ή-NMR (400 MHz, CDC) δ: 1.83 (quint, 2H, J = 5.7 Hz), 2.71 (s, 4H), 2.77 (t, 4H, J = 5.7 Hz), 3 70 (s, 4H), 3.93 (s, 6H), 3.96 (s, 12H), 7.24 (s, 4H), 7.56 (d, 2H, J = 8.1 Hz), 7.74 (dd, 2H, J = 8.1 Hz, 2.1 Hz), 8.60 (d, 2H, J = 2.1 Hz)

m / z (E I): 614 [M +]

Production Example 33

Synthesis of 2- (3,4,5-trimethoxyphenyl) pyridine_4-carbaldehyde

4-Hydroxymethyl-2- (3,4,5-trimethoxyphenyl) pyridine (1.01 g) is dissolved in benzene (10 mL), and activated manganese dioxide (purity 85%, 3.78 g) Was added. The mixture was stirred at room temperature for 5 hours, activated manganese dioxide (purity 85%, 3.78 g) was further added, and the mixture was stirred overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound.

Yield: 507mg (50%)

Ή-NMR (400 MHz, CDC ") (5: 3.92 (s, 3H), 3.99 (s, 6H), 7.32 (s, 2H), 7.62 (dd, 1 H, J = 4.9 Hz, 1.1 Hz), 8.09 (t, 1H, J = 1.1 Hz), 8.93 (del, 1 H, 1 = 4.9 Hz, 1.1 Hz), 10.16 (s , 1 H)

Production Example 34 Synthesis of 3- [2- (3,4,5-trimethoxyphenyl) pyridine-14-yl] ethyl probene:

Dissolve 2- (3,4,5-trimethoxyphenyl) pyridine-4-4-capillyl aldehyde (507 mg) and ethyl phosphonoacetate (570 iL) in tert-butanol (16 mL), and add potassium carbonate (438 mg). ) Was added. The mixture was stirred under reflux for 3 hours and concentrated under reduced pressure. The residue was dissolved in chloroform, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound.

Yield: 579mg (89%)

Ή-NMR (400MHz, CDC 1 3) (5: 1. 37 (t, 3H, J = 7. 7 Hz), 3. 92 (s, 3H), 3. 98 (s, 6 H), 4. 31 (q, 2H, J = 7.7Hz), 6.66 (d, 1H, J = 16.0Hz), 7.25 (s, 2H), 7.31 (dd, 1H, J = 5 1Hz, 1.6Hz), 7.68 (d, 1H, J = 16.0Hz), 7.72 (d, 1H, J = l. 6Hz), 8.70 (d, 1H, J = 5.1 Hz)

Production Example 35

Synthesis of 3- [2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] ethyl propionate:

3- [2- (3,4,5-trimethoxyphenyl) pyridine-4-yl] pro Ethyl penate (579 mg) was dissolved in methanol (20 mL), 10% palladium carbon (60 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound.

Yield: 52 lmg (90%)

Ή-NMR (400MHz, CDC 1 3) δ 1. 25 (t, 3H, J = 7. 1 Hz), 2. 70 (t, 2H, 1 = 7. 6Hz) 3. 02 (t, 2H, J = 7.6Hz), 3.90 (s, 3H), 3.97 (s6H), 4.15 (q, 2H, J = 7.1Hz), 7.08 (dd, 1H, J = 5.0 Hz, 16 Hz), 722 (s, 2H), 7.52 (d, 1 H, J = 1.6 Hz), 857 (d, 1 H, J = 5.0 Hz)

Production Example 36

Synthesis of 4- (3-hydroxypropyl) -1- (3,4,5-trimethoxyphenyl) pyridine:

3- (2- (3,4,5-Trimethoxyphenyl) pyridine-4-yl) ethyl propionate (52 lmg) was treated in the same manner as in Preparation Example 2 to obtain the title compound. Yield: 486mg (theoretical)

Ή-NMR (400MHz, CDC 1 3) (5: 1. 92 - 2. 00 (m, 2 H), 2. 80 (t, 2H, J = 7. 7Hz), 3. 73 (t, 2H, J = 6.2Hz), 3.90 (s, 3H), 3.97 (s, 6H), 7.08 (dd, 1H, J = 5.1 Hz, 1.7Hz), 7.22 (s, 2 H), 7.52 (dd, 1 H, J = l. 7 Hz, 0.7 Hz), 8.56 (dd, 1 H, J = 5.1 Hz, 0.7 Hz)

Production Example 37 Synthesis of 4- (3-methanesulfonyloxypropyl) -1-2- (3,4,5-trimethoxyphenyl) pyridine:

4- (3-Hydroxypropyl) -2- (3,4,5-trimethoxyphenyl) pyridine (486 mg) was dissolved in chloroform (10 mL), and methanesulfonyl chloride (186 AAL) and triethylamine were dissolved. (400 L) and stirred at room temperature overnight. The reaction solution was diluted with port-form, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound. Yield: 549mg (90%)

Example 19

Synthesis of N, N'-bis [3 -— [2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] propyl] piperazine'2 fumarate:

4- (3-Methanesulfonyloxypropyl) -2- (3,4,5-trimethyoxyphenyl) pyridine (259 mg) and piperazine (29 mg) were reacted in the same manner as in Example 1 to give the free base of the title compound. I got This was dissolved in methanol and fumaric acid was added to convert to the title compound.

Yield: 1 14mg (38%)

Ή-NMR (400 MHz, DMS〇-d ₆ , 120 ° C) δ 1.79—1.87 (m, 4H), 2.39 (t, 4H, J = 7. lHz), 2.47 ( s, 8H ), 2.70 (t, 4H, J = 7.3 Hz), 3.77 (s, 6H), 3.88 (s, 12H), 6.63 (s, 4H), 7.1 1 (dd , 2H, J = 4.9Hz, 1.6Hz), 7.34 (s, 4H), 7.67 (dd, 2H, J = 1.6Hz, 0.7Hz), 8.48 (dd , 2H, J = 4.9Hz, 0.7Hz) / z (EI): 654 [M +-2]

Example 20

Synthesis of N, N'-bis [3- [2-((3,4,5-trimethoxyphenyl) pyridine-1--4-yl] propyl] homopirazine / 2 fumarate:

4- (3-Methanesulfonyloxypropyl) -2- (3,4,5-trimethoxyphenyl) pyridine (261 mg) and homopidazine (34 mg) were reacted in the same manner as in Example 1 to release the title compound. The base was obtained. This was dissolved in methanol and converted to the title compound by adding fumaric acid.

Yield: 66mg (22%)

Ή-NMR (40 OMH z, DMSO- d 6, 120 ° C) <5: 1. 76 (qu int, 2H, J = 7. 9Hz), 1. 79 - 1. 87 (m, 4H), 2 57 (t, 4H, J = 7.1 Hz), 2.70 (t, 4H, J = 7.6Hz), 2.73 (t, 4H, J = 7.9Hz), 2.74 ( s, 4H), 3.77 (s, 6H), 3.87 (s, 12H), 6.61 (s, 4H), 7.10 (d, 2H, J = 4.6 Hz), 7. 34 (s, 4H), 7.66 (s, 2H), 8.47 (d, 2H, J = 4.9Hz)

m / z (EI): 668 [M ⁺ -2]

Production Example 38

2- (3,4,5_trimethoxyphenyl) pyridine-1-3-carbaldehyde Synthesis:

3-Hydroxymethyl-1- (3,4,5-trimethoxyphenyl) pyridine (958 mg) was treated in the same manner as in Production Example 33 to give the title compound.

Yield: 56 lmg (59%)

Production example 39

Synthesis of 3- [2- (3,4,5-trimethoxyphenyl) pyridin-3-yl] ethyl probene:

2- (3,4,5-Trimethoxyphenyl) pyridine-13-carbaldehyde (517 mg) was treated in the same manner as in Production Example 34 to obtain the title compound.

Yield: 74 Omg (theoretical)

Production 40

Synthesis of 3- [2- (3,4,5-trimethoxyphenyl) pyridin-3-yl] ethyl propionate:

Ethyl 3- [2- (3,4,5-trimethoxyphenyl) pyridine-3-yl] propanoate (74 Omg) was treated in the same manner as in Production Example 35 to give the title compound. Yield: 167mg (26%)

Ή-NMR (400MHz, CDC 1 3) (5: 1. 20 (t, 3H, J = 7. 1 Hz), 2.50 (t, 2H, J = 7.6Hz), 3.03 (t, 2H, J = 80Hz), 3.90 (s, 9H), 4.09 (q, 2H, J = 7.1 Hz), 669 (s, 2H), 7.23 (dd, 1H, J = 7.8Hz, 4.9Hz), 763 (del, 1H, J = 7.8Hz, 1 6Hz), 8.53 (cl d, 1 H, J = 4.8 Hz, 1.6 Hz)

Production Example 41

Synthesis of 3- (3-hydroxypropyl) -2- (3,4,5-trimethoxyphenyl) pyridine:

Ethyl 3- [2- (3,4,5-trimethoxyphenyl) pyridine-3-yl] propionate (167 mg) was treated in the same manner as in Preparation Example 2 to obtain the title compound. Yield: 1 35mg (9 1)

Ή-NMR (400 MHz, CDC 1 3) 6: 1. 75- 1. 83 (m, 2 H), 2. 78 (t, 2Η, J = 7. 9Hz), 3. 59 (t, 2H, J = 6.3 Hz), 3.88 (s, 6H), 3.89 (s, 3H), 6.69 (s, 2H), 7.22—7.24 (m, 1H), 7.64 (d, 1H, J = 7.6Hz), 8.51 (d, 1H, J = 3.3Hz)

Production Example 42

Synthesis of 3- (3-methanesulfonyloxypropyl) -1-2- (3,4,5-trimethoxyphenyl) pyridine:

3- (3-hydroxypropyl) 1-2- (3,4,5-trimethoxyphenyl) ) Pyridine (64 mg) was treated in the same manner as in Production Example 37 to give the title compound. Yield: 8 Omg (theoretical)

Example 21

Synthesis of N, Ν'-bis [3- [2- [3,4,5-trimethoxyphenyl] pyridine '3-yl] propyl] pidazine:

3- (3-Methanesulfonyloxypropyl) -2- (3,4,5-trimethoxyphenyl) pyridine (8 mg) and piperazine (9 mg) were reacted in the same manner as in Example 1 to release the title compound. Obtained as base.

Yield: 14mg (19%)

Ή-NMR (400MHz, C D C 1) δ 65 72 (m, 4H)

2. 24- 2.32 (m, 12 H), 2.68 (t, 4H, J = 8.0 Hz),

3.88 (s, 18H), 6.66 (s, 4H), 7.22 (dd, 2H, J = 7.7Hz, 4.6Hz), 7.62 (dd, 2H, J = 7.6Hz) , 1.5Hz), 8.50 (del, 2H, J = 4.8Hz, 1.7Hz)

m / z (E I): 654 [M + — 2]

Production Example 43

Synthesis of 2- (3,4,5-trimethoxyphenylethynyl) pyridine-4-ethyl carboxylate:

3,4,5-Trimethoxyphenylacetylene (1.80 g), 2-Chloroisonicotinic acid ethyl ester (2.08 g), and copper iodide (7 lmg) in DMF (4 mL) and triethylamine (8 mL) ), And then bis (triphenylphosphine) palladium dichloride (0) (13 lmg) was added, followed by stirring at 45 ° C for 4 hours under an argon atmosphere. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with 2 M hydrochloric acid, water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 1) to obtain the title compound.

Yield: 1.50 g (47%)

Ή-NMR (400MHz, CDC 1 3) δ: 1. 43 (t, 3H, J = 7. 1 Hz), 3. 88 (s, 6H), 3. 89 (s, 3 H), 4. 44 (q, 2 H, J = 7.1 Hz), 6.87 (s, 2H), 7.79 (dd, 1 H, J-5.1 Hz, 1.6 Hz), 8.07 (s, 2H) 1 H), 8.76 (d, 1 H, J = 5.1 Hz)

Production example 44

Synthesis of 2- (3,4,5-trimethoxyphenylethynyl) pyridine-4-carboxylic acid:

2- (3,4,5-Trimethoxyphenylethynyl) pyridine-41-ethyl ethyl ribonate (1.40 g) was suspended in methanol (100 mL), and hydrated lithium hydroxide (189 mg) was added. And stirred at room temperature. The reaction solution was concentrated under reduced pressure, water (3 OmL) was added to the residue, and the mixture was neutralized with 1M hydrochloric acid. After cooling on ice, the precipitated crystals were collected by filtration to give the title compound as colorless crystals.

Yield: 1.21 g (94%) Ή-NMR (400MHz, CDC 1 3) 6: 3. 79 (s, 3H), 3. 86 (s, 6H), 6. 98 (s, 2H), 7. 77 (dd, 1 H, J = 5.1 Hz, 1.7 Hz), 7.99 (s, 1 H), 8.55 (d, 1 H, J = 5.1 Hz) Manufacturing example 45

Synthesis of 4-hydroxymethyl-2- (3,4,5-trimethoxyphenylethynyl) pyridine:

2- (3,4,5-Trimethoxyphenylethynyl) pyridine-4 sorbonic acid (9 Omg) was dissolved in THF (6 mL) and triethylamine (35 mg) was added at 0 ° C under an argon atmosphere. . Next, ethyl chloroformate (34 mg) was added and the mixture was stirred for 1 hour. Ethyl acetate was added to the reaction solution, which was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in THF (2 mL), and at 0, an aqueous solution (ImL) of sodium borohydride (16 mg) was added, followed by stirring for 1 hour. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → ethyl acetate) to obtain the title compound.

Yield: 85mg (99%)

Ή-NMR (40 OMH z, CDC 1 3) δ 2. 06 (br, 1 Η), 3. 8 7 (s, 6Η), 3. 89 (s, 3 Η), 4. 76 (s, 2 Η), 6.85 (s, 2Η), 7.24 (d, 1Η, J = 5.1 Hz), 7.54 (s, 1H), 8.

57 (d, 1H, J = 5.1 Hz)

Production Example 46

Synthesis of 4-chloromethyl-2- (3,4,5-trimethoxyphenylethyl) pyridin:

4-Hydroxymethyl-2- (3,4,5-trimethoxyphenylethynyl) pyridine (483 mg) was treated in the same manner as in Preparation Example 3 to obtain the title compound.

Yield: 484mg (94%)

Ή-NMR (400 MHz, CDC 1 3) <5: 3. 88 (s, 6 H), 3. 89 (s, 3Η), 4. 58 (s, 2H), 6. 90 (s, 2Η) , 7.35 (d, 1Η, J = 5.1 Hz), 7.61 (s, 1 H), 8.63 (d, 1 H, J = 5.1 Hz)

Example 22

Synthesis of N, N'-bis [[2- (3,4,5-trimethoxyphenylethynyl) pyridin-1-yl] methyl] pidazine:

4-Chloromethyl-1- (3,4,5-trimethoxyphenylethynyl) pyridine (254 mg) and piperazine (31 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.

Yield: 182mg (78%)

Ή-NMR (400MHz, CDC 1 3) <5: 2. 52 (br, 8 H), 3. 5 2 (s, 4H), 3. 87 (s, 12 H), 3. 88 (s, 6H ), 6.85 (s, 4H), 7.22 (d, 2H, J = 4.1Hz), 7.52 (s, 2H), 8.40 (d, 2H, J = 5.1Hz) m / z (EI): 648 [M +]

Example 23

Synthesis of N, N'-bis [[2- (3,4,5-trimethoxyphenylethynyl) pyridin-1-yl] methyl] homopyrazine:

4-Chloromethyl-2_ (3,4,5-trimethoxyphenylethynyl) pyridine (230 mg) and homopirazine (32 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base. .

Yield: 67mg (31%)

Ή-NMR (400 MHz, CDC 1 3) δ: 1. 83- 1. 86 (m, 2 H), 2. 70 - 2. 78 (m, 8H), 3. 67 (s, 4H), 3 87 (s, 12H), 3.88 (s, 6H), 6.85 (s, 4H), 7.25 (d, 2H, J = 4.1 Hz), 7.52 (s, 2H) ), 8.54 (d, 2H, J = 4.1 Hz)

m / z (E I) 662 [M +]

Production 47

Synthesis of 4-hydroxy-6-methylpyrimidine:

4-Hydroxy-2-mercapto-16-methylpyrimidine (3.0 g) was dissolved in a mixed solution of ethanol (50 mL) and aqueous ammonia (10 mL). Raney nickel (R = 100, wet type, 6.0 g) was added and the mixture was stirred at 90 for 2 hours. After filtration using celite, the filtrate was concentrated under reduced pressure, water was added to the residue, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After drying, the mixture was concentrated under reduced pressure, and the crude crystals were recrystallized from chloroform-ether to give the desired compound.

Yield: 1.20 g (52%)

Ή-NMR (400MHz, CDC 1 3) (5: 2. 30 (s, 3H), 6. 29

(s, 1 H), 8.07 (s, 1 H)

Production Example 48

4 Synthesis of 6-methylpyrimidine: ^clx ir ^ ^Me

4-Hydroxy-1-methylpyrimidine (782 mg) was dissolved in phosphoryl chloride (6.6 mL), and the mixture was heated under reflux for 1 hour. The reaction solution was added dropwise to ice water, neutralized with a 2 M aqueous solution of sodium hydroxide, extracted with chloroform, the organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound. I got

Yield: 913mg (theoretical)

Production Example 49

4 Synthesis of monomethyl-6- (3,4,5-trimethoxyphenyl) pyrimidine:

4-Chloro-6-methylpyrimidine (913 mg) was reacted with 3,4,5-trimethyoxyphenylporonic acid (2.73 g) in the same manner as in Production Example 1 to obtain the title compound.

Yield: 92 Omg (50%)

Ή-NMR (400MHz, CDC 1 3) δ: 2. 51 (s, 3 H), 3. 84

(s, 3H), 3.88 (s, 6H), 7.25 (s, 2H), 7.44 (d, 1H, J = 0.6 Hz), 8.02 (d, 1H, J = 1.2 Hz) Synthesis of 6- (3,4,5-trimethoxyphenyl) pyrimidine-4-carboxaldehyde:

4-Monomethyl-16- (3,4,5-trimethoxyphenyl) pyrimidine (920 mg) was dissolved in dioxane (10 mL of O 2 OmL), selenium dioxide (784 mg) was added, and the mixture was stirred at 105 overnight. Water is added, extracted with ethyl acetate, the organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is purified by silica gel chromatography (hexane: ethyl acetate = 1: 1). The title compound was obtained. Yield: 492mg (51%)

Ή-NMR (400 MHz, CDC ") δ: 3.95 (s, 3H), 3.99 (s, 6H), 7.44 (s, 2H), 8.17 (d, 1 H, J = l .4Hz), 9.43 (d, 1H, J = 1.4Hz), 10.11 (s, 1H)

Production Example 51

Synthesis of 4-hydroxymethyl-6- (3,4,5-trimethoxyphenyl) pyrimidine:

6- (3,4,5-Trimethoxyphenyl) pyrimidine-41-carbaldehyde (364 mg) is dissolved in methanol (50 mL), sodium borohydride (25 mg) is added under ice-cooling, and the mixture is added at room temperature for 2 hours. Stirred. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform: methanol = 50: 1) to obtain the title compound.

50 Yield: 339mg (92%)

Ή-NMR (400 MHz, CDC) δ: 3.93 (s, 3H), 3.98 (s, 6H), 4.84 (s, 2H), 7.37 (s, 2H), 7.68 ( s, 1H), 9.18 (s, 1H)

Production Example 52

Synthesis of 4-chloromethyl-6- (3,4,5-trimethoxyphenyl) pyrimidine:

4-Hydroxymethyl-6- (3,4,5-trimethoxyphenyl) pyrimidine (339 mg) was dissolved in dichloromethane (20 mL), and thionyl chloride (0.15 mL) was added dropwise under ice-cooling, followed by stirring for 1 hour. . The reaction solution was neutralized with an aqueous sodium hydroxide solution, and extracted with methylene chloride. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound.

Yield: 174mg (60%)

Ή-NMR (400MHz, CDC 1 3) δ: 3. 86 (s, 3 H), 3. 91 (s, 6H), 4. 61 (s, 2H), 7. 30 (s, 2 H), 7.78 (s, 1 H), 9.10 (d, 1 H, J = 1.2 Hz)

Example 24

Synthesis of N, N'-bis [[6- (3,4,5-trimethoxyphenyl) pyrimidine-14-yl] methyl] pidazine:

4_Chloromethyl-6- (3,4,5-trimethoxyphenyl) pyrimidine (126 mg) and piperazine (18 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.

Yield: 99mg (77%)

Ή-NMR (400MHz, CDC 1 3) δ 2. 68 (br, 8H), 3. 7 3 (s, 4H), 3. 93 (s, 6 H), 3. 98 (s, 12 H), 7.37 (s, 4H), 7.79 (s, 2H), 9.16 (s, 2H)

mZz (EI): 602 [M ⁺ ]

Production Example 53

Synthesis of 2-bromo-4-monomethylpyrimidine:

2-Amino-4-methylpyrimidine (6.5 g) was dissolved in a small amount of water, and concentrated hydrochloric acid (30 mL) was added dropwise under ice cooling. Further, sodium nitrite (4.6 g) dissolved in water was added dropwise and stirred for 2 hours. Sodium bromide (30.6 g) dissolved in water was added dropwise, and the mixture was heated to room temperature and stirred for 4 hours. Extract with ethyl acetate, wash the organic layer with saturated brine, dry over sodium sulfate, concentrate under reduced pressure, purify the residue by silica gel chromatography (hexane: ethyl acetate = 9: 1), and purify the title compound. Obtained. Yield: 93 Omg (9%)

Ή-NMR (400 MHz, CDC 1 3) δ: 2. 55 (s, 3 H), 7. 13

(d, 1H, J = 5.1 Hz), 8.48 (d, 1H, J = 5.1 Hz) Production example 54 Synthesis of 4-Methyl-2- (3,4,5-trimethoxyphenyl) pyrimidine

2-Promo 4-methylpyrimidine (1.5 g) and 3,4,5-trimethoxyphenylporonic acid (1.83 g) were reacted in the same manner as in Production Example 1 to obtain the title compound.

Yield: 1.49 g (67%)

Ή-NMR (400MHz, CDC 1 3) δ: 2. 57 (s, 3H), 3. 92 (s, 3H), 3. 99 (s, 6H), 7. 01 (d, 1 H, J = 5.1 Hz), 7.77 (s, 2H), 8.61 (d, 1 H, J = 5.1 Hz)

Production Example 55

Synthesis of 2- (3,4,5-trimethoxyphenyl) pyrimidine-4 lipoaldehyde:

4-Methyl-2- (3,4,5-trimethoxyphenyl) pyrimidine (1.6 g) was treated in the same manner as in Production Example 50 to obtain the title compound.

Yield: 1.57 g (95%)

Ή-NMR (400MHz, CDC 1 3) (5:. 3. 87 (s, 3H), 3. 92 (s, 6H), 7. 56 (d, 1H, J = 4 9Hz), 7. 76 ( s, 2 H), 8.92 (d, 1 H, J = 4.7 Hz), 10.03 (s, 1 H)

Production Example 56

Synthesis of 4-hydroxymethyl-2_ (3,4,5-trimethoxyphenyl) pyrimidine:

2- (3,4,5-Trimethoxyphenyl) pyrimidine-14-carbaldehyde (1.27 g) was treated in the same manner as in Production Example 51 to obtain the title compound.

Yield: 1.00 g (78%)

Ή-NMR (400 MHz, CDC ") δ: 3.44 (br, 1H), 3.86 (s, 3H), 3.91 (s., 6H), 4.74 (d, 2H, J = 5.1 Hz), 7.10 (d, 1 H, J = 5.1 Hz), 7.59 (s, 2 H), 8.66

(d, 1 H, J = 5.1 H z)

Production Example 57

4 Synthesis of monochloromethyl-2- (3,4,5-trimethoxyphenyl) pyrimidine:

4-Hydroxymethyl_2- (3,4,5-trimethoxyphenyl) pyrimidine (1.00 g) was treated in the same manner as in Production Example 3 to obtain the title compound.

Yield: 1.05 g (98%)

Ή-NMR (400 MHz, CDC ") δ: 3.93 (s, 3H), 3.99 (s, 6H), 4.68 (s, 2H), 7.40 (d, 1 H, J = 5 1 Hz), 7.77 (s, 2H), 8.81 (d, 1 H, J = 5.1 Hz)

Example 25

Synthesis of N, N'-bis [[2- (3,4,5-trimethoxyphenyl) pyrimidine-14-yl] methyl] pidazine:

4-Monochloromethylyl 2- (3,4,5-trimethoxyphenyl) pyrimidine (

30 Omg) and piperazine (44 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.

Yield: 20 Omg (65%)

Ή-NMR (40 OMH z, CDC 1 3) 0 2. 60 (br, 8H), 3. 6 8 (s, 4H), 3. 84 (s, 6H), 3 91 (s, 12H), 7 30 (d, 2H, J = 5.1 Hz), 7.69 (s 4H), 8.64 (d, 2H, J = 5.1 Hz)

m / z (E I): 602 [M +]

Example 26

Synthesis of N, N'-bis [[2- (3,4,5-trimethoxyphenyl) pyrimidine-14-yl] methyl] homopyrazine:

4-Chloromethyl-1- (3,4,5-trimethoxyphenyl) pyrimidine (30 mg) and homopyrazine (51 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base. Was.

Yield: 269mg (87%)

Ή-NMR (400MHz, CDC 1 3) (5:. 1. 83- 1. 86 (m, 2H), 2. 79 (s, 4Η), 2. 82 (t, 4H, J = 6 OHz), 2.83 (s, 4H), 3.84 (s, 6H), 3.91 (s, 12H), 7.35 (d, 2H, J = 5.1 Hz), 7.70 (s , 4H), 8.65 (d, 2H, J = 5.1 H Z)

m / z (E I): 616 [M +]

Production Example 58

Synthesis of 2-methylthio-4- (3,4,5-trimethoxyphenyl) pyrimidine-15-carboxylate:

4-ethyl-2-methylthiopyrimidine-1-ethyl carboxylate (3.0 g) and 3,4,5-trimethoxyphenylporonic acid (2.73) were reacted in the same manner as in Production Example 1, The title compound was obtained.

Yield: 3 · 07 g (65%)

Ή-NMR. (400MHz, CDC ") δ: 1.09 (t, 3H, J = 7.1 Hz), 2.52 (s, 3H), 3.81 (s, 6H), 3.82 (s, 3H), 4.40 (q, 2H, J = 7.2Hz), 6.77 (s, 2H), 8.78 (s, 1H)

Production Example 59

Synthesis of 5-hydroxymethyl-2-methylthio-4- (3,4,5-trimethoxyphenyl) pyrimidine:

2-Methylthio-4- (3,4,5-trimethoxyphenyl) pyrimidine-15-carboxylate (2.51 g) was treated in the same manner as in Preparation Example 2 to obtain the title compound.

Yield: 72 Omg (38%) Ή-NMR (40 OMH z, CDC 1 3) δ: 2. 62 (s, 3 H), 3. 91 (s, 9H), 4. 68 (s, 2H), 7. 09 (s, 2H) , 8.61 (s, 1H)

Production Example 60

Synthesis of 5-hydroxymethyl-4- (3,4,5-trimethoxyphenyl) pyrimidine:

5-Hydroxymethyl-2-methylthio-4- (3,4,5-trimethoxyphenyl) pyrimidine (1.75 g) was dissolved in a mixed solution of ethanol (50 mL) and aqueous ammonia (5 mL). Raney nickel (R = 100, wet type, 17.0 g) was added, and the mixture was stirred at 90 for 2 hours and 30 minutes. The mixture was filtered using celite, the filtrate was concentrated under reduced pressure, water was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 9: 1) to obtain the title compound.

Yield: 827mg (50%)

Ή-NMR (400 MHz, CDC 1 3) δ 3. 91 (s, 9H), 4. 77 (s, 2H), 7. 04 (s, 2H), 8. 34 (s, 1 H), 9 . 18 (s, 1H)

Production Example 62

Synthesis of 5-chloromethyl-4- (3,4,5-trimethoxyphenyl) pyrimidine:

5-Hydroxymethyl-41 (3,4,5-trimethoxyphenyl) pyrimidine (827 mg) was treated in the same manner as in Production Example 3 to obtain the title compound.

Yield: 757mg (86%)

Ή-NMR (400 MHz, CDC 1 3) <5: 3. 93 (s, 3H), 3. 94 (s, 6H), 4. 65 (s, 2H), 7. 03 (s, 2 H) , 8.87 (s, 1 H), 9.22 (s, 1 H)

Example 27

Synthesis of N, N'-bis [[4- (3,4,5-trimethoxyphenyl) pyrimidine-1 5-yl] methyl] pidazine:

5-Chloromethyl-1- (3,4,5-trimethoxyphenyl) pyrimidine (25 mg) and piperazine (37 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base. Was.

Yield: 22 lmg (86%)

Ή-NMR (400MHz, CDC 1 3) δ 2. 53 (br, 8H), 3. 5 2 (s, 4H), 3. 92 (s, 18 H), 7. 17 (s, 4H), 8 . 72 (s, 2H), 9.12 (s, 2H)

m / z (EI): 602 [M ⁺ ]

Test example 1

(Cell adhesion inhibitory action)

The method was performed by referring to the method of Ross et al. (J. Biol. Chem., 267, 8537-8543 (1992)). That is, blood vessels derived from human umbilical vein Endothelial cells (HUVEC) are confluent in a 48-well plate (after culturing until complete,

1 L-1 / 3 or TNFa was added. Five hours after the addition, 1 × 10 ⁶ cells of U937, which is a cell derived from human monocyte Z histiocyte fluorescently labeled with PKH2 (Dainippon Pharmaceutical Co., Ltd.), were added to each well. After standing at room temperature for 1 hour, unadhered U937 was washed out, the cells were lysed with l% Triton X-100, and the remaining fluorescence intensity was measured (excitation wavelength 485 nm, measurement wavelength 530 nm). HUVEC is EGM—

2 (Sanko Junyaku) and U937 is 10 %% 3 content scale? ! ^ 1 Cultivated in 1640. Drug addition to HUVEC was performed at the time of IL-1 / 3 or TNFα addition, and to U937 was performed 24 hours before the cell adhesion test. Inhibitory activity was as follows: Α = (number of adherent cells of U937 to HUVEC stimulated with IL-1 / 3 or TNFα without addition of drug), B = (number of adherent cells of U937 to HUVEC stimulated without addition of drug) ), C = (the number of U937 adherent cells to HUVEC stimulated with IL-1 / 3 or TNFα by adding a drug) [100- (C-B) / (AB) X 100 (%)] Was calculated. Table 1 shows the results. As control compounds, test compound 1 of JP-A-9-143075 and dilazep of JP-A-11-92382 were simultaneously evaluated.

table 1

Inhibitory activity of each compound on cell adhesion at 1 M

Inhibition rate)

Example

TNF stimulation I L 1 1 i3 stimulation

4 43 42

9 64 53

10 71 63

22 50 34

Test compound 1 5 10

Dilazep 12 0

Hereinafter, specific formulation examples are shown. Formulation Example 1 (Capsule)

N, N'-bis [[2 -— (3,4,5-trimethoxyphenyl)

Pyridine [41-yl] methyl] piperazine 30 mg Microcrystalline cellulose 30 mg Lactose 30 mg Magnesium stearate 3 mg Total amount 93 mg After mixing the above components by a conventional method, the mixture was filled into a gelatin capsule to obtain a capsule.

Formulation Example 2 (tablet)

N, Ν '—bis [[2— (3,4,5-trimethoxyphenyl)

Pyridine-1-41] methyl] pidazine 30mg Starch 44mg Starch (for glue) 5.6mg Magnesium stearate 0.4mg Carboxymethylcellulose calcium 20mg Total amount 100mg The above components were mixed by a conventional method to obtain tablets.

Formulation Example 3 (injection)

N, Ν'-bis [[2- (3,4,5-trimethoxyphenyl) pyridine-4- [1yl] methyl] piperazine (l O Omg) and sodium chloride (900 mg) in about 8 OmL Dissolve in distilled water for injection, and add distilled water for injection to the resulting solution to make a total volume of 10 OmL. This was aseptically filtered, then dispensed into 10 light-shielded ampules and sealed to obtain a sterile injection. Industrial applicability The compound (1) of the present invention has an excellent inhibitory action on cell adhesion and cell invasion, and is useful as a preventive or therapeutic drug for allergy, asthma, rheumatism, arteriosclerosis, inflammatory disease and the like.

Claims

The scope of the claims

The following general formula (1)

(i)

A cyclic diamine compound represented by the formula: an acid addition salt thereof or a hydrate thereof.

2. A medicament comprising the cyclic diamine compound according to claim 1, an acid addition salt thereof or a hydrate thereof as an active ingredient.

3. The medicament according to claim 2, which is an agent for preventing or treating a disease caused by cell adhesion and / or cell invasion.

4. The medicament according to claim 3, wherein the disease is a disease selected from allergy, asthma, inflammation, rheumatism and arteriosclerosis.

5. A pharmaceutical composition comprising the cyclic diamine compound according to claim 1, an acid addition salt thereof or a hydrate thereof, and a pharmaceutically acceptable carrier.

6. The composition according to claim 5, which is used for prevention or treatment of a disease caused by cell adhesion and Z or cell infiltration.

7. The composition according to claim 6, wherein the disease is a disease selected from allergy, asthma, inflammation, rheumatism and arteriosclerosis.

8. Use of the cyclic diamine compound according to claim 1, an acid addition salt thereof or a hydrate thereof for the manufacture of a medicament.

9. The medicament is for the prevention or treatment of diseases caused by cell adhesion and Z or cell infiltration. 9. Use according to claim 8.

10. The use according to claim 9, wherein the disease is a disease selected from allergy, asthma, inflammation, rheumatism and arteriosclerosis.

1 1. A disease caused by cell adhesion and Z or cell infiltration characterized by administering an effective amount of the cyclic diamine compound according to claim 1, an acid addition salt thereof or a hydrate thereof to a patient in need thereof. Treatment method.

12. The treatment method according to claim 11, wherein the disease is a disease selected from allergy, asthma, inflammation, rheumatism, and arteriosclerosis.